Angiogenesis, the formation of new blood vessels from preexisting vessels, is a stepwise process involving vascular hyperpermeability, degradation of extracellular matrix, endothelial cell migration and proliferation, and formation and maturation of new capillary tubes. Whereas primary angiogenesis is a prominent feature of mammalian embryonic development, the normal adult body exhibits little vascular proliferation, with the exception of the female reproductive system and the cycling hair follicle. However, angiogenesis is a characteristic feature of inflammatory and neoplastic diseases and has been thought to represent a promising target for the development of novel anticancer therapies. While vascular endothelial growth factor (VEGF) has been suggested as the major skin and tumor angiogenesis factor, the biological function of placental growth factor (PlGF), an additional member of the vascular endothelial growth factor (VEGF) family of angiogenesis factors, has remained unknown. We recently found that two PlGF isoforms, PlGF-1 and PlGF-2, are upregulated in the chronic inflammatory skin disorder psoriasis and in squamous cell carcinomas of the skin, lesions that are characterized by richly angiogenic stroma. In vitro, epidermal PlGF expression is induced by transforming growth factor-alpha and by hypoxia, similar to VEGF. However, in contrast to VEGF, PlGF is also strongly expressed in dermal microvascular endothelial cells. PlGF-1 selectively activates the VEGF receptor-1 (VEGFR-1; Flt-1) on endothelial cells but not VEGFR-2 (KDR), in contrast to VEGF. PlGF-2 additionally binds to the neuropilin-1 receptor that is also shared by the neuronal guidance molecule semaphorin-D, acting as an antagonist. Recent findings in PlGF-deficient mice suggest that PlGF expression might be necessary for the biological activity of VEGF. To evaluate the importance of PlGF, alone or in concert with VEGF, in normal and pathological angiogenesis, we will investigate the following three aims: 1. Importance of PlGF in normal skin vascularization and in experimental skin inflammation, making use of PlGF-deficient mice, PlGF-2 transgenic mice, and of crosses with VEGF-transgenic mice. 2. Role of PlGF in the multistep process of skin carcinogenesis, elicited by a chemical carcinogen-promoter combination applied to normal, PlGF transgenic mice and PlGF-deficient mice. 3. Importance of transfected PlGF-1, PlGF-2, and semaphorin-D gene constructs for tumor growth, angiogenesis and metastasis of human squamous cell carcinoma and breast cancer xenotransplants. Understanding the molecular mechanisms that control skin and tumor angiogenesis will be the basis for the development of novel therapeutic approaches to treat inflammatory skin diseases and skin cancer.